Synthesis, biochemical and pharmacological properties of BUBUC, a highly selective and systemically active agonist for in vivo studies of delta-opioid receptors.

Based on the results of conformational studies of linear and cyclic delta-opioid peptides such as BUBU [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)] and DPLPE c[Tyr-D-Pen-Gly-Phe-Pen], a new enkephalin-related peptide, Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu) (BUBUC) was synthesized and tested for its opioid activity and selectivity at both the peripheral and central levels. Amongst all the synthetic compounds described so far, BUBUC appears to be the most highly delta-selective probe [KI (mu) = to 2980 nM, KI (delta): 2.9 nM, KI (mu)/KI (delta) approximately 1000]. This selectivity was confirmed by the results of pharmacological studies, including measurements of supraspinal analgesia and behavioral changes in mice. In the later test, BUBUC was shown to increase the rearing activity after IV administration at very low concentrations (0.1 mg/kg) and this effect was reversed by the delta-selective antagonist naltrindole. No antinociceptive response was observed at a 10-fold higher concentration. Thanks to its enzymatic stability and its hydrophobicity. BUBUC is the first systemically active, highly selective delta agonist and should therefore be useful to characterize the physiological role of delta-opioid receptors.